The pharmacological basis of nephrotoxicity resulting from analgesic abuse is being studied with several technics. The renal tubular transport of phenacetin and acetominophen, its major metabolite, occurs by passive diffusion. The conjugates of acetominophen undergo proximal bidirectional carrier mediated transport. Renal parenchymal levels of drug, with inulin as a reference marker, are consistent with the intracellular penetration of acetominophen, but not of its more polar conjugates. In mice and hamsters phenacetin and acetominophen depress glutathione levels in both the renal cortex and medulla. Our hypothesis is that high papillary concentrations of phenacetin and/or acetominophen during antidiuresis may undergo further intracellular metabolism to more toxic metabolites. Both the physiological and biochemical evidence to date support this. Further biochemical studies are in progress.